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EKV mutant connexin 31 associated cell death is mediated by ER stress

Daniel Tattersall1, Claire A Scott, Colin Gray

  • 1Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Human Molecular Genetics
|September 17, 2009
PubMed

Insights

Mutations in connexin 31 (Cx31) cause skin and nerve disorders. Researchers found that specific Cx31 mutations linked to erythrokeratoderma variabilis (EKV) induce cell death via endoplasmic reticulum (ER) stress and the unfolded protein response (UPR).

Area of Science:

  • Cell biology
  • Genetics
  • Dermatology

Background:

  • Connexin (Cx) proteins, particularly Cx31, are crucial for epidermal cell communication via gap junctions.
  • Mutations in Cx31 are linked to genetic disorders like erythrokeratoderma variabilis (EKV) and hearing loss, but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the cellular mechanisms by which Cx31 mutations associated with EKV and neuropathy lead to cell death.
  • To determine if abnormal hemichannel activity or endoplasmic reticulum (ER) stress is the primary driver of cell death.

Main Methods:

  • In vitro expression of wild-type (WT) Cx31 and disease-associated Cx31 mutants (R42P, C86S, G12D, 66delD).
  • Assessment of cell viability and cell-type specific cell death.
  • Immunocytochemistry to detect upregulation of unfolded protein response (UPR) components.

Main Results:

  • EKV-associated Cx31 mutants (R42P, C86S, G12D) induced significant cell death in vitro, unlike WT Cx31 or the neuropathy-associated mutant (66delD)Cx31.
  • Direct evidence ruled out leaky hemichannels as the primary cause of cell death.
  • Cells expressing EKV-associated Cx31 mutants showed increased levels of UPR components, indicating ER stress.

Conclusions:

  • Endoplasmic reticulum (ER) stress, leading to the unfolded protein response (UPR), is the principal mechanism driving cell death in Cx31-mutant associated diseases.
  • In EKV patients, ER stress may contribute to abnormal keratinocyte differentiation and hyperproliferation, characteristic of the skin disease.

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